Large studies reveal genes that dramatically influence schizophrenia risk

International research consortia have analyzed common and rare DNA variants in hundreds of thousands of people, revealing clearest genetic signals yet for schizophrenia risk.

Two landmark genetic studies on schizophrenia have just appeared together in the journal Nature.

The first study of more than 121,000 people, from an international consortium called SCHEMA, identified extremely rare protein-disrupting mutations in 10 genes that strongly increase an individual's risk of developing schizophrenia. A second, complementary study in a larger but overlapping group of 320,400 people, conducted by the Psychiatric Genomics Consortium (PGC), brings to 287 the number of regions of the genome associated with schizophrenia risk.

Together, these studies underscore an emerging view of schizophrenia as a breakdown in communication at the synapse (the junction between neurons), and illustrate how different kinds of genetic variation affecting the same genes can influence the risk for different psychiatric and neurodevelopmental disorders.

The SCHEMA and PGC findings are the fruit of a decade-long push led by researchers in the Stanley Center, Broad Institute of MIT and Harvard, and nearly fifty other institutions around the world, including the University of Helsinki and the Finnish Institute for Health and Welfare.

By working together, investigators across the PGC have built a dataset that now includes more than 320,400 people from collections across the world. The SCHEMA cohort comprises a subset of that, representing more than 121,000 people, including almost 1000 Finnish schizophrenia patients and more than 8000 controls. 

Rare but impactful risk variants

The SCHEMA (SCHizophrenia Exome Meta-Analysis) Consortium — which came together in 2017 — focuses on the exome, the nearly two-percent of the genome that encodes proteins. Specifically, the SCHEMA Consortium looked for variants that would either knock out or markedly alter a gene’s ability to produce functioning proteins.

By sequencing whole exomes from 24,248 people with schizophrenia and 97,322 without, the SCHEMA team identified ultra-rare variants in 10 genes that dramatically increased a person's risk of developing schizophrenia. These variants, called PTVs for “protein truncating variants,” prevent cells from producing a gene’s full-length functional protein.

"In general, any given person has a roughly one percent chance of developing schizophrenia in their lifetime," said Benjamin Neale from the Broad Institute of MIT and Harvard, one of the co-corresponding authors on the SCHEMA study. "But if you have one of these mutations, it becomes a 10, 20, even 50 percent chance."

Together, these genes point to dysfunction at the synapse — where neurons connect and communicate with each other — as a possible cause of schizophrenia. Two of the genes, GRIN2A and GRIA3, encode portions of the glutamate receptor, a cellular antenna found at the synapse that allows neurons to receive chemical signals from neighboring neurons.

Most of the SCHEMA genes, however, have never before been associated with a brain disorder or neuron-specific functions. One gene (SETD1A) is involved in transcriptional regulation. Another (CUL1) helps the cell recycle old or unneeded proteins, while yet another (XPO7) helps chaperone molecules out of the cell's nucleus. Yet in the SCHEMA analysis, PTVs in these genes drive a 20- to 52-fold increase in schizophrenia risk.

"We don't yet have a well-developed framework for understanding how these genes might play a role in schizophrenia," said SCHEMA co-corresponding author Mark Daly, a Director of the Institute for Molecular Medicine Finland (FIMM), University of Helsinki, and an institute member in the Broad Institute’s Stanley Center and Mass General ATGU faculty. "These genes will ultimately lead to some new insights, but are going to require a lot of experimental follow-up to see where they might fit in the puzzle."

The SCHEMA data also shed light on how psychiatric and neurodevelopmental disorders more broadly can share genetic risk. For instance, several SCHEMA genes, including GRIN2A, have previously been implicated with neurodevelopmental conditions such as epilepsy, developmental delay, and intellectual disability.

But by comparing their data from that of other large-scale studies, the SCHEMA team noted that the overlaps they saw were driven by different kinds of mutations: PTVs for schizophrenia, missense mutations for the neurodevelopmental conditions.

Emerging convergence

Separately, the PGC team examined common genetic variations in 76,755 people with schizophrenia and 243,649 without, finding 287 regions of the genome as having some involvement in schizophrenia risk, an increase of 94 loci since the last PGC analysis released in 2019.  With further analysis they identified 120 genes that potentially increase risk for schizophrenia. Several of these genes were also identified in the SCHEMA study.

However, the fact that both studies' findings converge similar groups of genes and similar biological mechanisms suggests that genetic discoveries are beginning to home in on core aspects of schizophrenia biology, and are close to broader insights into the mechanisms underlying schizophrenia progression.

"The biological complexity of schizophrenia is truly daunting, but this combination of rare protein altering variants from exome sequencing and common variants from GWAS have put us on our way to understanding the roots of that complexity," said Aarno Palotie, one of the co-authors of the study from the University of Helsinki. "In these results, we may be seeing how synaptic abnormalities or losses begin in schizophrenia, giving us openings to understand some of the fundamental, predisposing mechanisms that could guide us to means for earlier diagnosis and consequently earlier treatments than we can today."

"With schizophrenia, like with other complex disorders, I think we will ultimately find that many processes are involved in risk or protection," Daly added. "Understanding that may turn out to be one of the most complex undertakings in genetics and biology."

"We've tried for years and years to gain this kind of traction on the biology of schizophrenia," said Broad core institute member and Stanley Center director Steven Hyman. "Realistically, it will take yet more years to translate these results into biomarkers and treatments that will make a difference in the lives of people who are suffering with this devastating illness. But it is highly motivating to have a compelling path forward."

Original publications:

Singh TJ, Neale BM, Daly MJ, and the Schizophrenia Exome Meta-Analysis (SCHEMA) Consortium. Rare coding variants in 10 genes confer substantial risk for schizophrenia. Nature. Online April 8, 2022. DOI: 10.1038/s41586-022-04556-w.

The Schizophrenia Working Group of the Psychiatric Genomics Consortium, Ripke S, Walters JTR, and O’Donovan MC. Mapping genomic loci prioritises genes and implicates synaptic biology in schizophrenia. Nature. Online April 8, 2022. DOI: 10.1038/s41586-022-04434-5.

More information:

Read the whole press release from the Broad Institute here.

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